Association of plasma Protein C and CCL18 levels with neurodegenerative measures in Multiple Sclerosis patients

Background: Several studies suggested crosstalk among components of hemostasis, inflammation and immunity pathways in the pathogenesis and neurodegeneration in multiple sclerosis (MS). Methods: 138 MS patients and 42 healthy individuals (HI) were assessed with 3T MRI. Plasma levels of coagulation inhibitors (PC, TM, EPCR, PS, TFPI, PAI1), of chemokines (CCL18), and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, sVAP1), assayed by Multiplex and ELISA, were analyzed by partial correlation. Association of protein levels with MRI outcomes was performed by regression analysis. Results: In both MS patients and HI, levels of PC-CCL18, PC-PAI1, and PC-TFPI were correlated. Only in HI, levels of PC-PS, PS-PAI1, PS-VAP1 and PS-sVCAM1 were correlated. Only in MS patients, levels of TM were positively correlated with adhesion molecules, particularly with sICAM1, suggesting release from membranes favored by endothelial “injury”/alteration. In MS patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including brain parenchyma (p=0.002), gray matter (p<0.001), cortex (p=0.001), deep gray matter (p=0.001), and thalamus. These associations were detectable in relapsing remitting-MS but not in progressive-MS patients. The Multiplex assay was able to detect more efficiently activated PC (APC) than zymogen PC. However, the modest APC plasma concentrations would be masked by the 2-orders of magnitude higher concentration of inactive, zymogen PC in plasma. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p=0.03), and in the progressive-MS (p=0.003). In the progressive-MS, higher CCL18 levels were also associated with lower volumes of gray matter (p=0.024), cortex (p=0.043), deep gray matter (p=0.029), and thalamus (p=0.022). Conclusions: PC plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Disease-related PC pathway dysregulation is suggested by several protein level correlation differences between MS patients and HI. Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different stages of neurodegeneration. Taking into account that CCL18 is involved in immune cell chemotaxis, the correlation of PC with CCL18 levels, both associated with neurodegeneration, suggests a novel hemostasis-immune pathways relation